In Alzheimer's disease (AD), reactive glia surround amyloid plaques and produce pro-inflammatory mediators that activate neighboring glial cells as well as injure neurons which ultimately results in cognitive deterioration. The resulting neuron damage further activates the glia propagating a neuroinflammatory cycle. Our long-term goal is to investigate contributing factors to neuroinflammation and identify potential therapeutic targets for novel anti-inflammatories. The specific hypothesis for this proposal is that activated astrocytes near amyloid pathology produce the chemokine CCL2 which leads to increased neuroinflammation and neurodegeneration. This hypothesis is based on evidence that (a) CCL2 is found around amyloid plaques in AD brain, (b) CCL2 is upregulated in patients with mild AD, and (c) astrocytes produce CCL2 in response to amyloid beta (Abeta) in vitro. We will use two complementary in vivo models to determine 1) if astrocytes activated by Abeta produce CCL2 in vivo and the temporal and spatial relationship between CCL2 expression and AD-relevant neuroinflammation, and 2) if inhibition of CCL2 results in a decrease in neuroinflammation and neurodegeneration. [unreadable] [unreadable] [unreadable]